Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior

Avanti Gokhale, Cortnie Hartwig, Amanda A.H. Freeman, Julia L. Bassell, Stephanie A. Zlatic, Christie Sapp Savas, Trishna Vadlamudi, Farida Abudulai, Tyler T. Pham, Amanda Crocker, Erica Werner, Zhexing Wen, Gabriela M. Repetto, Joseph A. Gogos, Steven M Claypool, Jennifer K. Forsyth, Carrie E. Bearden, Jill Glausier, David A. Lewis, Nicholas T. SeyfriedJennifer Q. Kwong, Victor Faundez

Research output: Contribution to journalArticle

Abstract

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/- Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner.SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.

Original languageEnglish (US)
Pages (from-to)3561-3581
Number of pages21
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume39
Issue number18
DOIs
StatePublished - May 1 2019

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Systems Analysis
Synapses
Schizophrenia
Gene Dosage
Membrane Transport Proteins
Brain
Mitochondrial Membranes
Proteome
Synaptic Transmission
Oceans and Seas
Drosophila
Sleep
Fibroblasts
Mutation
Genes
Neurodevelopmental Disorders

Keywords

  • 22q11.2 microdeletion
  • mitochondria
  • schizophrenia
  • SLC25A1
  • SLC25A4
  • synapse

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior. / Gokhale, Avanti; Hartwig, Cortnie; Freeman, Amanda A.H.; Bassell, Julia L.; Zlatic, Stephanie A.; Sapp Savas, Christie; Vadlamudi, Trishna; Abudulai, Farida; Pham, Tyler T.; Crocker, Amanda; Werner, Erica; Wen, Zhexing; Repetto, Gabriela M.; Gogos, Joseph A.; Claypool, Steven M; Forsyth, Jennifer K.; Bearden, Carrie E.; Glausier, Jill; Lewis, David A.; Seyfried, Nicholas T.; Kwong, Jennifer Q.; Faundez, Victor.

In: The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 39, No. 18, 01.05.2019, p. 3561-3581.

Research output: Contribution to journalArticle

Gokhale, A, Hartwig, C, Freeman, AAH, Bassell, JL, Zlatic, SA, Sapp Savas, C, Vadlamudi, T, Abudulai, F, Pham, TT, Crocker, A, Werner, E, Wen, Z, Repetto, GM, Gogos, JA, Claypool, SM, Forsyth, JK, Bearden, CE, Glausier, J, Lewis, DA, Seyfried, NT, Kwong, JQ & Faundez, V 2019, 'Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior', The Journal of neuroscience : the official journal of the Society for Neuroscience, vol. 39, no. 18, pp. 3561-3581. https://doi.org/10.1523/JNEUROSCI.1983-18.2019
Gokhale, Avanti ; Hartwig, Cortnie ; Freeman, Amanda A.H. ; Bassell, Julia L. ; Zlatic, Stephanie A. ; Sapp Savas, Christie ; Vadlamudi, Trishna ; Abudulai, Farida ; Pham, Tyler T. ; Crocker, Amanda ; Werner, Erica ; Wen, Zhexing ; Repetto, Gabriela M. ; Gogos, Joseph A. ; Claypool, Steven M ; Forsyth, Jennifer K. ; Bearden, Carrie E. ; Glausier, Jill ; Lewis, David A. ; Seyfried, Nicholas T. ; Kwong, Jennifer Q. ; Faundez, Victor. / Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior. In: The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019 ; Vol. 39, No. 18. pp. 3561-3581.
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AU - Hartwig, Cortnie

AU - Freeman, Amanda A.H.

AU - Bassell, Julia L.

AU - Zlatic, Stephanie A.

AU - Sapp Savas, Christie

AU - Vadlamudi, Trishna

AU - Abudulai, Farida

AU - Pham, Tyler T.

AU - Crocker, Amanda

AU - Werner, Erica

AU - Wen, Zhexing

AU - Repetto, Gabriela M.

AU - Gogos, Joseph A.

AU - Claypool, Steven M

AU - Forsyth, Jennifer K.

AU - Bearden, Carrie E.

AU - Glausier, Jill

AU - Lewis, David A.

AU - Seyfried, Nicholas T.

AU - Kwong, Jennifer Q.

AU - Faundez, Victor

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